Ciano Albanese Naomi, Del Castillo Ignacio, Ragaglia Giulia, Castellano Giulia, Ajmone-Cat Maria Antonietta, De Simone Roberta, Griguoli Marilena, Ricceri Laura
Centre for Behavioural Science and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
Centre for Behavioural Science and Mental Health, Istituto Superiore di Sanità, Rome, Italy; European Brain Research Institute, Rome, Italy.
Brain Behav Immun. 2025 Oct;129:935-947. doi: 10.1016/j.bbi.2025.07.018. Epub 2025 Jul 29.
Risk for neurodevelopmental disorders can be related to early immune stimulations and altered brain microglial functions. Here we investigated the behavioural and electrophysiological effects of microglia depletion in a mouse model of developmental immune activation. C57BL/6J pregnant mice were exposed on gestational day 12.5 to polyinosinic:polycytidylic acid (Poly I:C), subsequently, on postnatal day 9, offspring was further treated with lipopolysaccharide (LPS). At weaning, offspring was exposed throughout adolescence (4 weeks) to either a diet containing Colony Stimulating Factor-1 receptor inhibitor (PLX5622, PLX) to reduce microglia, or standard diet. Hence, we assessed i) explorative and anxiety-like responses, social responsiveness and cognitive abilities between 7 and 8 postnatal week; ii) synaptic transmission and neuroinflammatory and microglial molecular markers in the medial prefrontal cortex (mPFC) and hippocampus (HP) at the end of treatment (8 postnatal week). EIA condition reduced locomotor activity and impaired discrimination between a familiar and a novel social stimulus (social novelty response) only in male mice. Also, PLX treatment selectively affected the same social novelty response in males (both saline and EIA) and in EIA females, intriguingly sparing saline females. Unexpectedly, EIA condition per se did not affect spontaneous excitatory and inhibitory synaptic transmission in both mPFC and HP, whereas EIA combined with PLX reduced inhibitory transmission in males (both mPFC and HP) and neuron excitability in both male and female mPFC. Interestingly, PLX had per se sex- and region- specific effects increasing inhibitory transmission in female mPFC and decreasing excitatory transmission in male HP. Molecular data, beside a robust downregulation of microglia markers in PLX diet groups, also showed that EIA condition increased interleukin-6 (il-6) expression in EIA males in both mPFC and HP, and elevated il-1β levels in both sexes in mPFC and in male HP. Overall, these findings indicate that males have an increased vulnerability to the long-term behavioural and inflammatory effects of the EIA condition, and are more likely to exhibit behavioural and electrophysiological changes in response to microglia depletion.
神经发育障碍的风险可能与早期免疫刺激和脑小胶质细胞功能改变有关。在此，我们在发育性免疫激活小鼠模型中研究了小胶质细胞耗竭的行为和电生理效应。C57BL/6J 孕鼠在妊娠第 12.5 天暴露于聚肌苷酸:聚胞苷酸（Poly I:C），随后，在出生后第 9 天，子代进一步用脂多糖（LPS）处理。在断奶时，子代在整个青春期（4 周）暴露于含有集落刺激因子-1 受体抑制剂（PLX5622，PLX）的饮食以减少小胶质细胞，或标准饮食。因此，我们评估了：i）出生后第 7 至 8 周之间的探索性和焦虑样反应、社交反应性和认知能力；ii）在治疗结束时（出生后第 8 周）内侧前额叶皮质（mPFC）和海马体（HP）中的突触传递以及神经炎症和小胶质细胞分子标记物。EIA 条件仅在雄性小鼠中降低了运动活动并损害了对熟悉和新社交刺激的辨别能力（社交新奇反应）。此外，PLX 处理选择性地影响了雄性（盐水处理组和 EIA 组）和 EIA 雌性小鼠中的相同社交新奇反应，有趣的是盐水处理的雌性小鼠未受影响。出乎意料的是，EIA 条件本身并未影响 mPFC 和 HP 中的自发兴奋性和抑制性突触传递，而 EIA 与 PLX 联合使用则降低了雄性（mPFC 和 HP）中的抑制性传递以及雄性和雌性 mPFC 中的神经元兴奋性。有趣的是，PLX 本身具有性别和区域特异性效应，增加了雌性 mPFC 中的抑制性传递并降低了雄性 HP 中的兴奋性传递。分子数据显示，除了 PLX 饮食组中小胶质细胞标记物的强烈下调外，还表明 EIA 条件增加了 EIA 雄性小鼠 mPFC 和 HP 中的白细胞介素-6（il-6）表达，并提高了 mPFC 中两性以及雄性 HP 中的 il-1β 水平。总体而言，这些发现表明雄性对 EIA 条件的长期行为和炎症影响更为敏感，并且更有可能表现出对小胶质细胞耗竭的行为和电生理变化。
